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Emerging evidence indicates that microRNAs (miRNAs) play fundamental roles in the pathogenesis of multiple diseases, including acute lung injury (ALI). Here, we discovered that miR-199a-3p was significantly downregulated in ALI lung tissues using a microarray analysis. In vitro lipopolysaccharide (LPS) treatment of the human epithelial cell line A549 and the human macrophage cell line U937 caused a decrease of miR-199a-3p. Mechanically, miR-199a-3p specifically bound to the 3'-untranslated region (3'-UTR) of NLRP1 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 1), a critical member of inflammasomes. Ectopic overexpression or downregulation of miR-199a-3p resulted in the repression or induction of NLRP1 , respectively, thereby downregulating or activating its downstream events. Moreover, transcription factor FOXP3 (forkhead box P3) was able to specifically bind to the promoter of miR-199a-3p. Knockdown or overexpression of FOXP3 resulted in a decrease or induction miR-199a-3p expression, respectively. Using immunoprecipitation (IP), mass spectrometry and co-IP assays, we found that FOXP3 formed a transcriptional complex with HDAC1 (histone deacetylase 1) and CtBP2 (C-terminal-binding protein 2). Collectively, our results suggested that the CtBP2-HDAC1-FOXP3 transcriptional complex (CHFTC) could specifically bind to the promoter of miR-199a-3p and repress its expression. Downregulation of miR-199a-3p eliminated its inhibition of NLRP1 , causing activation of NLRP1 and cleavage of pro-IL-1β and pro-IL-18 mediated by Caspase-1. The secretion of IL-1β and IL-18 further aggravated the inflammatory response and resulted in the occurrence of ALI.

Downregulation of miR-199a-3p mediated by the CtBP2-HDAC1-FOXP3 transcriptional complex contributes to acute lung injury by targeting NLRP1